Influence of early life physical inactivity during a key period of postnatal development on adult muscle quality – from matrix to mortality - Project Summary The physical inactivity (PIA) epidemic has far-reaching negative health impacts on adults, but even more so on children, who are facing more PIA than ever in diverse forms. Although the detrimental impacts of PIA on postnatal muscle are pronounced, and the negative impacts on bone are well established across the lifecycle, the impact of early-life PIA on muscle and metabolic health in adulthood is not fully realized. Thus, our objectives are 1) to investigate the effect of the level of early-life physical inactivity in mice on the muscle quality and function phenotype in adulthood, 2) to determine the root of muscle quality losses by examining the regulatory aspects of the extracellular matrix (ECM) in adulthood, 3) to investigate the effect of the level of early-life physical inactivity on frailty development and survival and 4) to expose undergraduate students to meritorious biomedical research methods. We have piloted early-life PIA experiments, physical performance tests, immunofluorescence methods, and data analysis with undergraduate researchers and are prepared to complete this proposal. We have preliminary data indicating that brief (2wk) early life PIA in mice produces weaker muscles, reduced muscle quality, increased ECM, and decreased muscle macrophages 5 months later as adults. This equates to about half a year of PIA during the first few years of life and early adulthood is about 25-30y of age for a human. Our preliminary data suggest a concerning trajectory potentially characterized by attenuated muscle quality and function -- all of which are associated with premature aging and the possibility of rapid development of frailty and reduced lifespan. Thus, we aim to characterize how the level of early life PIA, roughly equivalent to ~6 months human child, will contribute to muscle quality (ECM changes) and physical function losses resulting from brief (2 weeks) early life PIA during a key period of development in early adulthood (6 mo). The early life PIA will be conducted with three levels of intensity with muscle disuse, reduced activity, and sedentary cage activity compared to active control with running wheel access. We will examine skeletal muscle ECM collagen content and structure, muscle macrophages, and ECM regulation in adult male and female mice exposed to brief early-life PIA. Lastly, we will use physical performance testing throughout aging to examine the effect of the development of frailty and survival curves in mice exposed to brief early-life PIA
